In this study, we investigated the effects of isorhamnetin on myocardial ischaemia reperfusion (I/R) injury in Langendorff-perfused rat hearts. Isorhamnetin treatment (5, 10 and 20 μg/mL) significantly alleviated cardiac morphological injury, reduced myocardial infarct size, decreased the levels of marker enzymes (LDH and CK) and improved the haemodynamic parameters, reflected by the elevated levels of the left ventricular developed pressure (LVDP), coronary flow (CF) and the maximum up/down velocity of left ventricular pressure (+dp/dtmax ). Moreover, isorhamnetin reperfusion inhibited apoptosis of cardiomyocytes in the rats subjected to cardiac I/R in a dose-dependent manner concomitant with decreased protein expression of Bax and cleaved-caspase-3, as well as increased protein expression of Bcl-2. In addition, I/R-induced oxidative stress was manifestly mitigated by isorhamnetin treatment, as showed by the decreased malondialdehyde (MDA) level and increased antioxidant enzymes activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). These results indicated that isorhamnetin exerts a protective effect against I/R-induced myocardial injury through the attenuation of apoptosis and oxidative stress.

The mtDNA copy number can affect the function of mitochondria and play an important role in the development of diseases. However, there are few studies on the mechanism of mtDNA copy number variation and its effects in IS. The specific mechanism of mtDNA copy number variation is still unclear. In this study, mtDNA copy number of 101 IS patients and 101 normal controls were detected by qRT-PCR, the effect of D-loop variation on mtDNA copy number of IS patients was explored. Then, a TFAM gene KD-OE PC12 cell model was constructed to explore the effect of mtDNA copy number variation on mitochondrial function. The results showed that the mtDNA copy number level of the IS group was significantly lower than that of the normal control group (p < 0.05). The relative expression of TFAM gene mRNA in the cells of the OGD/R treatment group was significantly lower than that of the control group (p < 0.05). In addition, after TFAM gene knockdown and over-expression plasmids were transfected into HEK 293T cells, mtDNA copy number and ATP production level of Sh-TFAM transfection group was significantly decreased (p < 0.05), while mtDNA copy number and ATP production level of OE-TFAM transfected group were significantly higher than that of blank control group and OE-ctrl negative control group (p < 0.01). Our study demonstrated that mitochondrial D-loop mutation and TFAM gene dysfunction can cause the decrease of mtDNA copy number, thus affecting the mitochondrial metabolism and function of nerve cells, participating in the pathological damage mechanism of IS.

Numerous microRNAs participate in regulating the pathological process of atherosclerosis. We have found miR-130a is one of the most significantly down-regulated microRNAs in arteriosclerosis obliterans. Our research explored the function of miR-130a in regulating proliferation by controlling autophagy in arteriosclerosis obliterans development. A Gene Ontology (GO) enrichment analysis of miR-130a target genes indicated a correlation between miR-130a and cell proliferation. Thus, cell cycle, CCK-8 assays and Western blot analysis were performed, and the results indicated that miR-130a overexpression in vascular smooth muscle cells (VSMCs) significantly attenuated cell proliferation, which was validated by an in vivo assay in a rat model. Moreover, autophagy is thought to be involved in the regulation of proliferation. As our results indicated, miR-130a could inhibit autophagy, and ATG2B was predicted to be a target of miR-130a. The autophagy inhibition effect of miR-130a overexpression was consistent with the effect of ATG2B knockdown. The results that ATG2B plasmids and miR-130a mimics were cotransfected in VSMCs further confirmed our conclusion. In addition, by using immunohistochemistry, the positive results of LC3 II/I and ATG2B in the rat model and artery vascular tissues from the patient were in accordance with in vitro data. In conclusion, our data demonstrate that miR-130a inhibits VSMCs proliferation via ATG2B, which indicates that miR-130a could be a potential therapeutic target that regulates autophagy in atherosclerosis obliterans.

Relapse-specific mutations in phosphoribosyl pyrophosphate synthetase 1 (PRPS1), a rate-limiting purine biosynthesis enzyme, confer significant drug resistances to combination chemotherapy in acute lymphoblastic leukemia (ALL). It is of particular interest to identify drugs to overcome these resistances. In this study, we found that PRPS1 mutant ALL cells specifically showed more chemosensitivity to 5-Fluorouracil (5-FU) than control cells, attributed to increased apoptosis of PRPS1 mutant cells by 5-FU. Mechanistically, PRPS1 mutants increase the level of intracellular phosphoribosyl pyrophosphate (PRPP), which causes the apt conversion of 5-FU to FUMP and FUTP in Reh cells, to promote 5-FU-induced DNA damage and apoptosis. Our study not only provides mechanistic rationale for re-targeting drug resistant cells in ALL, but also implicates that ALL patients who harbor relapse-specific mutations of PRPS1 might benefit from 5-FU-based chemotherapy in clinical settings.

Diabetic foot ulcer (DFU) is one of the common ailments of elderly people suffering from diabetes. Exosomes containing various active regulators have been found to play a significant role in apoptosis, cell proliferation and other biological processes. However, the effect and the underlying mechanism of action of diabetes patients derived from circulating exosomes (Dia-Exos) on DFU remain unclear. Herein, we aim to explore the potential regulatory role of Dia-Exos. First, we attempted to demonstrate the harmful effect of Dia-Exos both in vivo and in vitro. miRNA-24-3p (miR-24-3p) was found enriched with Dia-Exos. Hence, inhibition of this miRNA could partially reverse the negative effect of Dia-Exos, thus, in ture, accelerates wound repair. Luciferase assay further verified the binding of miR-24-3p to the 3'-UTR of phosphatidylinositol 3-kinase regulatory subunit gamma (PIK3R3) mRNA and the PIK3R3 expression enhanced human umbilical vein endothelial cells functionality in vitro. Hence, the findings of this study reveal the regulatory role of Dia-Exos in the process of wound healing and provide experimental evidence for the therapeutic effects of knocking down miR-24-3p in DFU treatment.

Patients with relapsed/refractory Burkitt's lymphoma (BL) have a dismal prognosis. Current research efforts aim to increase cure rates by identifying high-risk patients in need of more intensive or novel therapy. The 8q24 chromosomal translocation of the c-Myc gene, a main molecular marker of BL, is related to the metabolism by regulating phosphoribosyl pyrophosphate synthetase 2 (PRPS2). In our study, BL showed significant resistance to thiopurines. PRPS2 homologous isoenzyme, PRPS1, was demonstrated to play the main role in thiopurine resistance. c-Myc did not have direct effects on thiopurine resistance in BL for only driving PRPS2. PRPS1 wild type (WT) showed different resistance to 6-mercaptopurine (6-mp) in different metabolic cells because it could be inhibited by adenosine diphosphate or guanosine diphosphate negative feedback. PRPS1 A190T mutant could dramatically increase thiopurine resistance in BL. The interim analysis of the Treatment Regimen for Children or Adolescent with mature B cell non-Hodgkin's lymphoma in China (CCCG-B-NHL-2015 study) confirms the value of high-dose methotrexate (MTX) and cytarabine (ARA-C) in high-risk paediatric patients with BL. However, there remains a subgroup of patients with lactate dehydrogenase higher than four times of the normal value (4N) for whom novel treatments are needed. Notably, we found that the combination of thiopurines and the phosphoribosylglycinamide formyltransferase (GART) inhibitor lometrexol could serve as a therapeutic strategy to overcome thiopurine resistance in BL.